DESCRIPTION (taken from the application) Persistent H. pylori infection is an important etiologic factor for the development of atrophic gastritis and gastric adenocarcinoma; however, only a small percentage of infected persons develop neoplasia. Enhanced cancer risk may be related to differences in expression of specific bacterial products, differences in host response to the bacteria, or both. H. pylori strains that possess cagA are associated with increased severity of gastritis and with additional risk for developing atrophic gastritis and cancer. One mechanism contributing to neoplastic transformation may be inhibition of epithelial cell apoptosis, a process regulated by transcription factors such as NF-KappaB and p53. Our hypothesis is that the increased malignant potential of H. pylori cagA+ strains is dependent on the ability to selectively affect eukaryotic proteins that regulate multiple cellular pathways which results in both heightened inflammation and decreased apoptosis. Since the effect of H. pylori on programmed cell death is likely to be complex, this project is being submitted as one component of an interactive proposal with Dr. Duane Smoot of Howard University. Dr. Smoot's in vitro studies will primarily focus on downstream effectors of NF-KappaB-dependent apoptosis such as nitric oxide, reactive oxygen intermediates, and Bc1-2 related proteins which will complement our experiments on H. pylori and NF-KappaB in gastric epithelial cells and gastric mucosa. This collaborative approach should facilitate elucidation of specific mechanisms by which H. pylori alters apoptosis and predisposes infected individuals to carcinogenesis. The long-term objective of this proposal is to examine the molecular mechanisms by which H. pylori strains selectively affect apoptosis in vitro and in vivo. First, we plan to determine whether wild-type H. pylori strains of varying genotype differentially affect NF-KappaB dependent apoptosis, using an in vitro model of gastric epithelial cell interaction with H. pylori. Using isogenic mutant strains containing inactivation cassettes within cagA, picA, picB, vacA, and iceA, we also will determine the role of specific H. pylori virulence determinants in eukaryotic apoptosis. Second, we will determine the effect of wild-type and isogenic H. pylori mutant strains on gastric epithelial cell apoptosis and NF-KappaB-dependent apoptosis in vivo using a rodent model of infection. Third, we will examine the effect of H. pylori on mediators of gastric epithelial cell apoptosis in vivo in p53-deficient mice. From these studies, as well as from Dr. Smoot's experiments, we can begin to dissect the pathways that are activated in gastric epithelial cells following interaction with H. pylori that may play a role in the subsequent development of gastric cancer.